Treatment of malignant gliomas and brain metastases in adults using a combination of adriamycine, VM 26, and CCNU. Results of a type II trial.

Forty-three patients with inoperable and/or recurring malignant gliomas and 30 patients with multiple recurring brain metastases were treated with a combination of adriamycine (45 mg/m 2 and 4-dimethyl-epipodophyllotoxin D-thenylidene (VM 26) (60 mg/m 2 for 2 days) and 1-(2-chloroethyl)-3-cyclohexyl-1-nitroso-urea (CCNU) (60 mg/m 2 for 2 days). These cycles of treatment were repeated as soon as the hematologic restoration was complete. The treatment was well-tolerated and the clinical condition of 31 out of 43 glioblastoma patients improved during the 2 months after the beginning of the treatment. Six out of eight patients with breast cancer metastases, one out of 13 with bronchial cancer metastases, and three out of nine with other types of cancer metastases also benefitted from the treatment. Examination of the results reveals the following characteristics: 1. A low degree of efficiency of this combination in the treatment of brain metastases, except for breast cancer metastases. 2. Absence of complete correlation between the clinical results observed and the cinegammagraphic developments 3. Similarity of the results independent of the initial localization 4. Establishment of a 6-month median survival period, with ten patients at present in a state of apparently complete remission, 180-506 days after beginning of the treatment.

[Treatment of inoperable glioblastomas using a combination of adriamycin, VM 26 and CCNU]. / Traitement des glioblastomes inopérables par une combinaison d'adriamycine, de VM 26 et de CCNU

46 non resectable malignant gliomas adult patients were treated with a combination protocol of chemotherapy with administration of adriamycin, VM 26 and CCNU. The tolerance to this treatment was good except for the delayed hematological toxicity related to cumulative doses of CCNU, which limited after 5 courses of chemotherapy the possibility of further treatment with the same combination. As far as the neurological responses are concerned, 66 per 100 patients were good responders, but we found a poor relation (50%) between the degree of clinical response and regression of tumour volume in brain scan. The median survival of this group of patients was 9 months and 11 patients/46 are still alive in good state 14 months after they entered into this trial. According to these data we discuss the introduction of chemotherapy at the early stage of the disease.

Post-surgical outcome of 57 patients with Mycobacterium xenopi pulmonary infection.

The outcome of 57 surgically treated cases with pulmonary infection due to Mycobacterium xenopi was studied. Success without any complications was observed in 21 patients while complications were observed in the other 36, during the 1st year (early complications) after surgery in 26 patients and after the 1st year (late complications) in 10. Early complications included two deaths, four relapses, two treatment failures, six cases of respiratory impairment, four cancers and 21 immediate post-operative complications which required 19 supplementary operations. Early complications were more frequent (p less than 0.05) in patients with pleural and/or emphysematous lesions. Late complications included 10 deaths, eight relapses, four pulmonary infections and five cancers. They were more frequent (p less than 0.05) in patients with the following risk factors: under nutrition, smoking/alcohol abuse, gastric ulcers with or without gastrectomy, associated serious illness, respiratory impairment and extensive pre-surgical radiographic lesions. In no case was infection due to M. xenopi directly responsible for lack of improvement.

[Isolated azygos continuation of the inferior vena cava]. / La continuation azygos isolée de la veine cave inférieure.

The finding, on systemic X-ray examination of a 20-years ol Algerian patient, of an opaque image along the right side of the suprahilar trachea led to the discovery of a rare abnormality of venous return known as azygos continuation of the inferior vena cava. The opacity was ovoid in shape, 4 X 1.7 cm in dimension, well circumscribed and homogeneous. It shrunk during a Valsalva's manoeuvre and increased in size when the patient was lying down. Angiography through the femoral vein showed that the inferior vena cava was interrupted below the liver and continued with the azygos vein. No other cardiovascular abnormality was detected and the situs was normal. Although rare or unrecognized because it is asymptomatic, azygos continuation of the inferior vena cava is the most common of congenital abnormalities of that vessel. It was described initially by Stark in 1835 and remained an anatomical curiosity until 1950. Since the development of vascular opacification techniques, it has been more frequently diagnosed, particularly in children, where it is usually associated with congenital heart disease and/or abnormal situs. Our case is peculiar in that no congenital abnormalities were present.

Transmission of tubercle bacilli: The effects of chemotherapy.

The important differences in the infectivity of the various forms of tuberculosis can be explained by quantitative data concerning the behaviour of the tubercle bacillus in man and the number of bacilli in the lesions and sputum. Patients in whom tubercle bacilli can be detected by direct examination of the sputum smear are the main sources of transmission. Moreover the individuals infected by them break down more often with the disease. In the individual patient, the use of antibacterial drugs completely changes the natural history of the disease: not only do patients no longer die but they are cured; their period of infectivity is considerably reduced, relapses are avoided, chronicity disappears. The drugs used prophylactically in individuals of high risk groups prevent development of the disease. The impact of chemotherapy is reflected by a two-to-three-fold increase in the speed of decline of the risk of infection, a decline which had started before the introduction of the drugs. While patients given the right combination of drugs lose their infectivity in a few weeks (probably most often in less than two weeks), treatment must of course be continued much longer and regularly in order to ensure the maintenance of conversion and the absence of relapse. This stresses the importance of providing means to ensure the taking of the drugs by all patients. The future reduction of transmission will essentially depend on the maintenance of an adequate system ensuring the early diagnosis and correct treatment of cases, which will inevitably continue to appear among the already infected portion of the population. Epidemiological surveillance is mandatory as well as the surveillance of the delivery of services, particularly of the quality of diagnosis and therapeutic services. The roles of public health authorities and perhaps still more that of the practising physician, specialized and not specialized, remain considerable both from an epidemiological point of view and from the point of view of the relief of all the suffering still created by the disease.

[Adjusting or not adjusting isoniazid dosage?]. / Adapter ou ne pas adapter la posologie de l'isoniazide?

Between the 24 October 1977 and the 31 December 1978 a series of 299 patients were treated with triple therapy--Rifampicin, Ethambutol and Isoniazid; the latter was given in a standard dose of 5 mg/kg. Between the 1 January 1979 and the 31 December 1981 a second series of 448 patients were treated with the same combination, Isoniazid was given in a dose adjusted for acetylator status (Vivien et coll.). In all the patients the serum concentration of Isoniazid at 3, 6 and 12 hours (after a single oral dose of 5 mg/kg) were measured and the two series of patients were comparable. No significant difference was noted between the two groups regarding either efficacy or toxicity. The adjustment of Isoniazid dosage according to acetylator status has not resulted in any statistically significant benefit in those patients studied.

Combined chemotherapy including rifabutin for rifampicin and isoniazid resistant pulmonary tuberculosis. G.E.T.I.M. (Group for the Study and Treatment of Resistant Mycobacterial Infection).

A prospective multicentre open study has been conducted in France in order to assess the efficacy and tolerability of an antimycobacterial regimen including rifabutin in the treatment of patients with pulmonary tuberculosis due to rifampicin and isoniazid resistant bacilli. Patients were treated with daily rifabutin (450-600 mg), associated with companion drugs to which the organisms remained susceptible; in most cases the regimen included a fluoroquinolone. The duration of treatment was initially scheduled for a minimum period of 12 months after sputum culture conversion. Thirty nine patients were enrolled, 23 of whom were treated for at least 12 months. Culture conversion was obtained at the end of the twelfth month in 14 out of 23 patients. Twenty one out of 39 patients experienced adverse events. These were, however, serious enough to discontinue treatment in only four patients. These results suggest that an antimycobacterial combination including rifabutin might contribute to the treatment of multi-resistant pulmonary tuberculosis.

Rifabutin in combination with clofazimine, isoniazid and ethambutol in the treatment of AIDS patients with infections due to opportunist mycobacteria. Groupe d'Etude et de Traitement des Infections à Mycobacteries Résistantes.

96 AIDS patients with fever and either acid-fast bacilli on microscopic examination of bacteriological samples or mycobacteria isolated by culture were treated with a daily 4-drug combination of 7-10 mg/kg rifabutin, 5 mg/kg isoniazid, 20 mg/kg ethambutol and 100 mg clofazimine. 46 patients were excluded from efficacy assessment: 13 died before or within the first days of treatment, 5 had negative initial cultures, 14 had initial cultures positive for M. tuberculosis, 4 for M. kansasii, 1 for M. flavescens, 1 for M. gordonae, 7 were lost to follow-up and 1 received no rifabutin. In the 50 remaining patients, 31 had disseminated disease due to M. avium intracellulare complex (MAIC) and 19 had apparently localised disease, due to MAIC in 15 cases and to M. xenopi in 4 cases. Side-effects led to withdrawal of isoniazid in 1 case (hepatic enzymes increased) and rifabutin in another (thrombocytopenia). After 1 month of treatment, fever decreased from 38.4 +/- 0.6 degrees C to 37.7 +/- 0.5 degrees C (p less than 0.01) and patients stopped losing weight. After 3 months treatment, only 37 patients were alive and still under treatment. Cultures became negative in 16 of 23 patients with available bacteriological data (9 of 14 patients with disseminated disease and 7 of 9 patients with localised disease), relapse occurred before death in 4 patients. 34 patients died before treatment was completed. Death was considered to be related to mycobacterial infection in 5 cases. We conclude that the 4-drug combination is safe and, in some cases, it appears to be effective.

[Trial treatment of glioblastomas in adults and cerebral metastais by adriamycin, VM 26 and CCNU combination. Result of a type II trial]. / Essai de traitement des glioblastomes de l'adulte et des métastases cérébrales par l'association d'adriamycine, de VM 26 et de CCNU. Résultats d'un essai de type II

Forty-three patients with inoperable and/or recurring malignant gliomas, and 30 patients with multiple recurring brain metastases were treated with a combination of adriamycine (45 mg/m2) and 4-dimethyl-epipodophyllotoxin D-thenylidene (VM 26) (60 mg/m2 for 2 days) with 1-(2-chloroethyl) -3-cyclohexyl-1-nitroso-urea (CCNU) (60 mg/m2 for two days). These cycles of treatment were repeated as soon as the hematological restoration was complete. The treatment was well tolerated and the clinical condition of 31 out of 43 glioblastoma patients improved during the two months after the beginning of the treatment. Six out of eight patients with breast cancer metastases, one out of 13 with bronchial cancer metastases and three out of nine with other types of cancer metastases also benefitted from the treatment. Examination of the results obtained reveals the following characteristics: -A low degree of efficiency of the combination in the treatment of brain metastases, except for breast cancer metastases. -Absence of complete correlation between the clinical results observed and the cinegammagraphic developments. -Similarity of the results independent of the initial localization. -Establishment of a six-months median survival period, with ten patients at present in a state of apparently complete remission, 180 to 506 days after beginning of the treatment.

[Chemotherapeutic combinations of mutually potentiating drugs. 3-Application to primary tumors of the central nervous system]. / Combinaisons chimiothérapiques de grogues se potentialisant. III. Application aux tumeurs primitives du systeme nerveux central

17 patients suffering from primary tumours of the central nervous system recurring after surgery and/or radiotherapy, received chemotherapy consisting of the administration of VM 26 followed by CCNU. Each cycle of treatment lasted four days and was restarted only after an average interval of 30 days to allow for haematological recovery. All of the patients in the trial have been under treatment for eight months. Five (28 p.cent) are at present in complete remission with no residual clinical, isotopic or radiological signs. In six others there was tumour regression and in four neurological stabilisation. In all those cases where objective tumour regression was obtained functional improvement was noted.

[Chemotherapeutic combinations of mutually potentializing drugs. 1-Application to the treatment of breast cancers]. / Combinaisons chimiothérapiques de drogues se potentialisant. I. Application au traitement des cancers du sein

27 patients suffering from disseminated carcinoma of the breast with at least two visceral metastases, and two had become resistant to conventional chemotherpy and hormones, received a combination of, in the present trial, vincristine followed by cyclophosphamide with 5-fluoro-uracil. Chemotherapy was administered intermittently: each cycle of treatment lasted 6 days and was followed by a period without treatment of 25 days. Haematological tolerance was satisfactory. No serious incidents occurred during two years use of the combination. 20 out of 27 patients showed objective tumour regression of more than 50 p.cent lasting for more than 6 months, whilst 9 showed apparent complete regression of the malignant lesions. There was one complete failure. Chemotherapy was continued in all cases after regression of the neoplastic process was obtained.

[Chemotherapeutic combinations of mutually potentiating drugs. 2-Application to the treatment of bronchial cancers]. / Combinaisons chimiothérapiques de drogues se potentialisant. II. Application au traitement des cancers bronchiques

16 patients suffering from primary bronchial tumours which had recurred after surgery and/or radiotherapy and with spread involving at least one visceral or lymphatic metastasis received chemotherapy consisting of the administration of vincristine followed by a combination of CCNU and 5-fluorouracil. Each cycle of treatment lasted 6 days and was restarted only after an interval of 30 days on average, this being necessary for haematological recovery. With the doses of CCNU used, thrombocytopaenia occurred only during the fifth cycle of treatment and made it necessary to increase the interval between subsequent courses to five weeks. All of the patients included in the study have now been followed up for between six and eighteen months. Two patients are presently in complete remission without apparent radiological, clinical or bronchoscopic signs. In seven other patients there was tumour regression greater than 50 p.cent persisting for four to six months. In seven, the therapeutic effect was transient or nil.

[Correlation between immunological stage and response to chemotherapy. Results in 64 patients with nonresectable epidermoid bronchial cancers]. / Relation entre l'état immunitaire et la réponse à la chimiothérapie. Résultats chez 64 malades avec cancers bronchiques épidermoïdes inopérables

Out of 64 patients with non resectable epidermal bronchus carcinoma, 26 patients had before any treatment positive responses of skin tests to recall antigens. In these patients we found a correlation between the reactivity of the skin tests, the presence of seric factor inhibiting the leucocyte migration, the mean count of peripheral lymphocytes and the response to combination chemotherapy protocol. The patients who respond to treatment have a significantly better prognosis than the patients who do not respond. With this correlation it seems to be possible to distinguish between two populations of patients with non resectable bronchus carcinoma : one population with a good risk who can be significantly improved by the treatment : the other population with a very severe prognosis.